Although the etiology of inflammatory bowel disease (IBD) is unknown, an immunologic pathogenesis is strongly suggested by the pathology of the lesions. We have postulated that a disorder of immunoregulation in the intestine might be the basic underlying defect in the pathogenesis of IBD, and we have been focusing our efforts on studies of regulatory T cells in the intestine. We have recently found that lamina propria T8 cells have prominent contrasuppressor activity, an activity with great potential relevance for IBD. In this proposal we plan to continue to exam the functional activities of the regulatory T4 and T8 subsets from the lamina propria of patients with IBD. We will then extend these studies by creating regulatory T cell hybridoma clones that can be rigorously examined in vitro. These hybridoma studies will focus particularly on isotype-specific regulation and on contrasuppression by lamina propria T-hybridoma clones, which represent important questions in mucosal immunity in general and in IBD in particular. In addition, the hypothesis that IBD may be due to altered immunoregulation will be directly tested by assessing the immune response of patients with IBD and of normal controls to oral immunization with cholera toxin b subunit as a model intestinal antigen. This will be the first study of oral immunization to a defined antigen ever done in these patients. Lastly, we plan to study the antigen-specific regulation of the immune response to cholera toxin B subunit of patients with IBD and of normal controls, after oral immunization.